1. Targeting Colorectal Cancer with Conjugates of a Glucose Transporter Inhibitor and 5-Fluorouracil.
- Author
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Chang CK, Chiu PF, Yang HY, Juang YP, Lai YH, Lin TS, Hsu LC, Yu LC, and Liang PH
- Subjects
- Animals, Antineoplastic Agents metabolism, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Cell Survival drug effects, Colorectal Neoplasms chemically induced, Colorectal Neoplasms drug therapy, Colorectal Neoplasms metabolism, Disease Models, Animal, Drug Stability, Enzyme Inhibitors metabolism, Enzyme Inhibitors pharmacology, Enzyme Inhibitors therapeutic use, Fluorouracil therapeutic use, Glucose Transport Proteins, Facilitative metabolism, Half-Life, Humans, Mice, Mice, Inbred BALB C, Phloretin chemistry, Phloretin metabolism, Phloretin therapeutic use, Phlorhizin chemistry, Phlorhizin metabolism, Phlorhizin therapeutic use, Structure-Activity Relationship, Tissue Distribution, Antineoplastic Agents chemistry, Enzyme Inhibitors chemistry, Glucose Transport Proteins, Facilitative antagonists & inhibitors
- Abstract
Overexpression of glucose transporters (GLUTs) in colorectal cancer cells is associated with 5-fluorouracil ( 1 , 5-FU) resistance and poor clinical outcomes. We designed and synthesized a novel GLUT-targeting drug conjugate, triggered by glutathione in the tumor microenvironment, that releases 5-FU and GLUTs inhibitor (phlorizin ( 2 ) and phloretin ( 3 )). Using an orthotopic colorectal cancer mice model, we showed that the conjugate exhibited better antitumor efficacy than 5-FU, with much lower exposure of 5-FU during treatment and without significant side effects. Our study establishes a GLUT-targeting theranostic incorporating a disulfide linker between the targeting module and cytotoxic payload as a potential antitumor therapy.
- Published
- 2021
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